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A randomized, placebo-controlled trial to evaluate the tolerability, safety, pharmacokinetics, and pharmacodynamics of a potent inhibitor of poly(ADP-ribose) polymerase (INO-1001) in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: results of the TIMI 37 trial

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Abstract

Background Reperfusion injury is a significant complication of the management of ST-elevation MI (STEMI). INO-1001 is a potent inhibitor of poly(ADP-ribose) polymerase (PARP), a mediator of oxidant-induced myocyte dysfunction during reperfusion. Methods & results We assessed the safety and pharmacokinetics of INO-1001 in a randomized, placebo-controlled, single-blind, dose-escalating trial in 40 patients with STEMI undergoing primary percutaneous coronary intervention within 24 h of onset. INO-1001 was well-tolerated. A trend toward more frequent transaminitis was observed with 800 mg. Plasma from INO1001-treated patients reduced in vitro PARP activity >90% at all doses. Serial C-reactive protein and IL-6 levels showed a trend toward blunting of inflammation with INO-1001. The apparent median terminal half-life (t1/2) of INO-1001 was 7.5 (25th, 75th: 5.9, 10.2) h. Conclusions The results from this first trial of INO-1001 in STEMI support future investigation of INO-1001 as a novel treatment for reperfusion injury.

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Acknowledgments

TIMI 37A was supported by the NIH R44 HL074684-01 and by Inotek Pharmaceuticals Corporation.

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Authors and Affiliations

  1. TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham & Women’s Hospital, 75 Francis Street, Boston, MA, 02115, USA

    David A. Morrow, Sabina A. Murphy, Laura Grip & Carolyn H. McCabe

  2. Inotek Pharmaceuticals, Beverly, MA, USA

    Chaim M. Brickman, Sujatha Kumar, Natanya Slomowitz & Andrew L. Salzman

  3. Saint Paul Heart Clinic, St. Paul, MN, USA

    Kenneth Baran

  4. Assaf Harofeh Medical Center, Tel Aviv, Israel

    Ricardo Krakover

  5. Fletcher Allen Health Care, University of Vermont College of Medicine, Burlington, VT, USA

    Harold Dauerman

Authors
  1. David A. Morrow
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  2. Chaim M. Brickman
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  3. Sabina A. Murphy
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  4. Kenneth Baran
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  5. Ricardo Krakover
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  6. Harold Dauerman
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  7. Sujatha Kumar
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  8. Natanya Slomowitz
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  9. Laura Grip
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  10. Carolyn H. McCabe
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  11. Andrew L. Salzman
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Corresponding author

Correspondence to David A. Morrow.

Additional information

Clinical trial registration: NCT 00271765 at www.clinicaltrials.gov.

Appendix

Appendix

TIMI Study Group, Brigham and Women’s Hospital, Boston, MA

Eugene Braunwald (Study Chairman), Carolyn H. McCabe (Director), David A. Morrow (Principal Investigator), Laura Grip (Project Manager), Sabina A. Murphy (Statistical group).

Inotek Pharmaceuticals, Beverly, MA (Sponsor)

Andrew L. Salzman (CEO and President), Chaim M. Brickman (Director of Clinical Operations), Sujatha Kumar (Scientist), Natanya Slomowitz (Biometrics Manager).

Enrolling Sites

United States: Atassi K (PI), Christy L (RC), Porter Hospital, Valparaiso, IN; Baran K (PI), Canniff J (RC), Jorgenson B (RC), St. Paul Heart Clinic, St. Paul, MN; Dauerman H (PI), Chadwick L (RC), Straight F (RC), Fletcher Allen Health Care, Burlington, VT; Glaser R (PI), Mannion T (RC), Willhide J (RC), University of Pennsylvania Medical Center, Philadelphia, PA; Hartman C (PI), Bullivant M (RC), Mulvihill R (RC), Sentara Norfolk General Hospital, Norfolk, VA; Nahhas A (PI), Winston N (RC), Toledo Hospital, Toledo, OH; Niederman A (PI), Kellerman T (RC), The Greater Fort Lauderdale Heart Group Research, Ft. Lauderdale, FL.

Israel: Gruberg L (PI), Ben Tzevi M (RC), Rambam Medical Center, Haifa; Krakover R (PI), Ribak S (RC), Assaf Harofeh Medical Center, Zerifin; Kornowski R (PI), Shor N (RC), Rabin Medical Center, Petach Tikva.

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Morrow, D.A., Brickman, C.M., Murphy, S.A. et al. A randomized, placebo-controlled trial to evaluate the tolerability, safety, pharmacokinetics, and pharmacodynamics of a potent inhibitor of poly(ADP-ribose) polymerase (INO-1001) in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: results of the TIMI 37 trial. J Thromb Thrombolysis 27, 359–364 (2009). https://doi.org/10.1007/s11239-008-0230-1

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  • DOI: https://doi.org/10.1007/s11239-008-0230-1

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